Diabetes mellitus (type 1 and type 2 diabetes) is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. About 5% of all people suffer from diabetes and the disorder approaches epidemic proportions. Since the discovery of insulin in the 1920's, continuous efforts have been made to improve the treatment of diabetes mellitus. Since people suffering from diabetes are subject to chronic treatment over several decades, there is a major need for safe, convenient and life quality improving insulin based therapeutics.
Human insulin consists of two polypeptide chains, the so-called A and B chains which contain 21 and 30 amino acid residues. An insulin analogue is human insulin wherein one or more of the amino acids have been exchanged with other amino acids. Some of the commercial available insulin formulations are characterized by a fast onset of action and other formulations have a relatively slow onset but show a more or less prolonged action.
Treatment of type 1 and type 2 diabetes typically includes treatment with a long acting basal insulin for between meal and nocturnal glycemic control together with treatment with a short-acting preprandial bolus insulin for meal stimulated hyperglycemia. The goal for the treatment is maintenance of long-term near normoglycemic control.
Conjugation of a therapeutic peptide or protein such as insulin to human serum albumin or derivatives thereof results in protection of the therapeutic peptide or protein against proteases. The increased size of the therapeutic results in reduced clearance. Conjugation thereby results in a prolonged residence time of the conjugate (see WO 01/77137 and WO 2006/012346). Conjugation of insulin to albumin results in a prolonged action profile and thereby a reduction in injection frequency. The maintenance of near normo-glycemia results in a lower risk of hypo-glycemia (vide Diabetes 2005, vol 54, 251-258, and Bioconjugate Chem. 2005, vol 16, 1000-1008).
Claim 7 in WO 00/69900 relates to a method for protecting a therapeutic peptide from peptidase activity comprising, e.g., forming a peptide-blood component conjugate where the blood component according to claim 14 is albumin. None of the specific examples in WO 00/69900 deals with insulin.
Claim 1 in WO 2005/012346 relates to an insulin derivative comprising an insulin molecule and a reactive group for covalently bonding a blood component. According to claim 2 therein, the reactive group is coupled to an amino acid of the insulin molecule, i.e., human insulin, at a position selected from the positions Gly A1, Phe B1 and Lys B29.
Claim 1 in WO 2005/103087 relates to a method for separating albumin conjugate from unconjugated albumin. The insulins exemplified in WO 2005/103087 are human insulin and insulins having extensions on A1, B1 or B29, all containing A21Asn (A21N).
Claim 1 in WO 2007/071068 relates to a process for preparation of a conjugate comprising albumin covalently linked to a compound. Insulin is mentioned at page 9, line 16, therein. No specific examples are given in WO 2007/071068.
Normally, insulin formulations are administered by subcutaneous injection.